(Circulation. 1999;100:967-973.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Requirement for Protein Kinase C in Reactive Oxygen Species–Induced Apoptosis of Vascular Smooth Muscle Cells
From the Department of Cardiology, Franz Volhard Clinic, Humboldt University Berlin, and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Correspondence to Rüdiger von Harsdorf, MD, Franz-Volhard-Klinik, Universitätsklinikum Charité, Humboldt-Universität, Wiltbergstraße 50, 13125 Berlin, FRG. E-mail rharsdo{at}mdc-berlin.de
Background—Vascular smooth muscle cell (VSMC) apoptosis is a component of a variety of cardiovascular diseases and may be related to reactive oxygen species (ROS). This study was designed to determine the role of protein kinase C (PKC) in ROS-induced VSMC apoptosis.
Methods and Results—Rat aortic VSMCs were exposed to
H2O2, and the nature of cell death was
characterized in the absence or presence of different PKC
inhibitors. The results demonstrate that exposure of VSMCs
to H2O2 led to a dose-dependent (25 to 100
µmol/L) and time-dependent (peak at 2 minutes) activation of PKC.
Among the PKC isoforms 
, ß, 
, 
, and 
, only PKC- and
PKC- were found to change their intracellular distribution on
H2O2 treatment. Apoptosis was the
predominant form of cell death when PKC had been activated by
H2O2 alone or by H2O2
in the presence of 50 nmol/L phorbol 12-myristate 13-acetate.
In contrast, necrosis became the predominant form of cell death when
PKC had been downregulated by prolonged exposure to 200 nmol/L phorbol
12,13-dibutyrate or inhibited by 50 nmol/L staurosporine,
100 nmol/L calphostin C, or 30 µmol/L H-7. In addition,
caspase-3 was activated in H2O2-induced
VSMC apoptosis but not when PKC was downregulated or inhibited.
Inhibition of caspase-3 by 50 µmol/L Ac-DEVD-CHO could
significantly attenuate H2O2-induced
apoptosis and was not associated with the induction of
necrosis.
Conclusions—We conclude that in VSMCs, PKC converts the ROS-induced signals from necrotic cell death to the activation of an apoptotic cell death program. These data imply a novel and important role of PKC for the pathogenesis of such vascular diseases as atherosclerosis, restenosis, and hypertension.
Key Words: muscle, smooth • cells • free radicals • apoptosis • kinase • caspase
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